Method for producing methyl-4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate

Abstract

The present invention relates to a method for producing methyl-4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate of formula (II) by reacting it with diphosgene or triphosgene in the presence of one or more solvents and catalysts, wherein, with respect to diphosgene, the reaction is between methyl-4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) and diphosgene The present invention relates to a method wherein the molar ratio of is in the range of 1.0:0.5 to 1.0:2.25; or, with respect to triphosgene, the molar ratio of methyl-4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is in the range of 1.0:0.333 to 1.0:1.5; and the molar ratio of methyl-4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0:0.01 to 1.0:2.0. TIFF2026511628000011.tif65138

Description

Technical Field

[0001] The present invention relates to a novel method for preparing methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate, which is known as an intermediate for the synthesis of the herbicide thienecarbazone-methyl (DE19933260).

Background Art

[0002] It is known that methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate can be prepared by reacting methyl 4-(chlorosulfonyl)-5-methylthiophene-3-carboxylate with a metal cyanate in the presence of imidazole (WO2018 / 153767). To prepare the target product, the sulfochloride was reacted with 1-2 equivalents of sodium cyanate in the presence of 1-1.5 equivalents of N-methylimidazole. The resulting product was reacted directly to obtain thienecarbazone-methyl either by a one-pot method or a two-step method. Thienecarbazone-methyl was obtained in a yield of 76-84%.

[0003] It is also known that methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate can be prepared from the corresponding sulfonamide by phosgenation in the absence of an organic base and optionally in the presence of a catalyst (WO2006 / 072376). To prepare the target product, the sulfonamide was reacted with 2.4 equivalents of excess phosgene in the presence of n-butyl isocyanate or pentyl isocyanate. The product was obtained in a yield of 83% in both cases.

[0004] In addition to phosgene, triphosgene has also been used in the literature for the synthesis of sulfonyl isocyanates. However, the reported synthesis is undesirable in several respects. They yield the desired product in either low yield (ChemCatChem (2020), 12(17), 4352-4372), require long reaction times (WO2015 / 061518), or use large amounts of triphosgene (Nongyao (2015), 54(2), 83-87). In some cases, two or more of the aforementioned harmful aspects apply (Journal of the American Chemical Society 2009, 131(25), 8754-8755).

[0005] When evaluating a chemical process, various factors must be considered. On the one hand, many factors influence the economic viability of a process. Important factors in this regard include, for example, the availability and price of the raw materials and solvents used, the quantities of raw materials and solvents used, and especially the process yield and product quality. Another important element in process evaluation is the issue of process safety. Key aspects of process safety include, for example, toxicity, environmental hazard, the physical and chemical properties of the hazardous substances used, and precise process conditions such as temperature, pressure, addition order, and timing. These points determine the safety concepts necessary for industrial implementation in production facilities.

[0006] Phosgene is a highly toxic gaseous hazardous substance. Inhalation of phosgene is always expected to pose an acute risk to life. Therefore, the use of phosgene should be kept to a minimum. Because it involves high safety requirements, the corresponding processes are complex and therefore costly.

[0007] Triphosgene is also toxic. However, in contrast to phosgene, it is a solid. In principle, phosgene is released from triphosgene only in the reactor. Triphosgene can be added dropwise to the reaction solution as a solution in a controlled manner. Thus, phosgene release is localized and controlled. This significantly reduces the risk of gas release. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] WO2018 / 153767 [Patent Document 2] WO2006 / 072376 [Patent Document 3] WO2015 / 061518 [Non-patent literature]

[0009] [Non-Patent Document 1] ChemCatChem(2020),12(17),4352-4372 [Non-Patent Document 2] Nongyao(2015),54(2),83-87 [Non-Patent Document 3] Journal of the American Chemical Society 2009,131(25),8754-8755 [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] Considering the prior art described, there has been a continuing need for an improved, industrially and economically viable method for producing methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate. In this regard, the methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate obtained by this method should preferably be obtained in high yield and high chemical purity. Furthermore, this method should reduce the use of toxic and harmful substances (e.g., phosgene), solvents, and other additives compared to the prior art. [Means for solving the problem]

[0011] Surprisingly, it was found that when diphosgene or triphosgene is used instead of phosgene in the synthesis of methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate, the yield can be increased when the same amount of phosgene equivalent is used.

[0012] Furthermore, it was discovered that the reaction could be carried out at higher concentrations (with less solvent) by simultaneously reducing the amount of catalyst used. This is even more surprising, as increasing the concentration without simultaneously reducing the amount of catalyst results in a decrease in yield and product purity.

[0013] Therefore, the present invention is based on formula (II): [ka]

[0014] By reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate with diphosgene or triphosgene in the presence of one or more solvents and catalysts, formula (I) is obtained: [ka]

[0015] A method for preparing methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate, wherein - with respect to phosgene, the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to phosgene is within the range of 1.0:0.5 to 1.0:2.25; or - with respect to triphosgene, the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is within the range of 1.0:0.333 to 1.0:1.5; and the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is within the range of 1.0:0.01 to 1.0:2.0, relating to the said method.

[0016] To increase the yield, the molar ratio between methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) and the catalyst can be selected according to the concentration of the reactant of formula (II) in the reaction solvent.

[0017] At a concentration of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate at the start of the reaction within the range of more than 5% by weight to 10% by weight, the preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is within the range of 1.0:0.5 to 1.0:2.0, particularly preferably within the range of 1.0:0.7 to 1.0:1.8.

[0018] At a concentration of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate at the start of the reaction within the range of more than 10% by weight to 15% by weight, the preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is within the range of 1.0:0.3 to 1.0:1.8, particularly preferably within the range of 1.0:0.5 to 1.0:1.6.

[0019] At the start of the reaction, the concentration of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate is in the range of over 15% by weight to 20% by weight. The preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0:0.1 to 1.0:1.6, and particularly preferably in the range of 1.0:0.3 to 1.0:1.4.

[0020] At the start of the reaction, the concentration of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate is in the range of over 20% by weight to 30% by weight. The preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0:0.01 to 1.0:1.4, and particularly preferably in the range of 1.0:0.1 to 1.0:0.8.

[0021] At the start of the reaction, the concentration of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate is in the range of over 30% by weight to 40% by weight. The preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0:0.01 to 1.0:1.2, and particularly preferably in the range of 1.0:0.05 to 1.0:0.7.

[0022] At the start of the reaction, the concentration of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate is in the range of over 40% to 50% by weight. The preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0:0.01 to 1.0:1.0, and particularly preferably in the range of 1.0:0.05 to 1.0:0.6.

[0023] Advantageously, methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate of formula (I) can be prepared in very good yield and very good quality by the method according to the present invention. Furthermore, the method according to the present invention overcomes further drawbacks arising from the prior art.

[0024] The method according to the present invention can be described by the following scheme (1): Scheme (1) [ka]

[0025] The compound of formula (II) can be obtained, for example, by the method described in DE19933260.

[0026] General definition In the following, "alkyl" in the present invention preferably means linear, branched, or cyclic hydrocarbons having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylpropyl, 1,3-dimethylbutyl, 1,4-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 2-ethylhexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0027] In this patent application, the term "equivalent" is understood to mean "molar equivalent" in all cases unless otherwise specified in a particular example.

[0028] The term "phosgene equivalent" as used in this patent application is based on the following relationship: 1 equivalent of triphosgene corresponds to 3 phosgene equivalents; 1 equivalent of diphosgene corresponds to 2 phosgene equivalents.

[0029] In this patent application, the term "industrial xylene" is understood to mean a mixture of o-xylene, m-xylene, p-xylene, and ethylbenzene.

[0030] Method explanation: Methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate (formula (II)) is reacted in the presence of one or more solvents to obtain methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate.

[0031] Suitable solvents include, in particular, tetrahydrofuran (THF), dioxane, diethyl ether, diglyme, methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME), ethylene glycol dimethyl ether (DME), 2-methyl-THF, acetonitrile (ACN), butyronitrile, ethyl acetate, isopropyl acetate, butyl acetate, pentyl acetate, methyl isobutyl ketone, ethylene carbonate, propylene carbonate, N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), N-methylpyrrolidone, sulfolane; halogenated hydrocarbons, especially chlorinated hydrocarbons and fluorinated hydrocarbons, such as tetrachloroethylene, tetrachloroethane, dichloropropane, dichloromethane (DCM), dichlorobutane, chloroform, trichlorotrifluoroethane, and tetrachloride. Carbon, trichloroethane, trichloroethylene, pentachloroethane, 1,2-dichloroethane; aromatic hydrocarbons and halogenated hydrocarbons, such as difluorobenzene, benzotrifluoride, 4-chlorobenzotrifluoride, benzene, toluene, anisole, o-xylene, m-xylene, p-xylene, industrial xylene, ethylbenzene, mesitylene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, chlorobenzene, bromobenzene, dichlorobenzene, especially 1,2-dichlorobenzene, chlorotoluene, trichlorobenzene, cumene; aliphatic hydrocarbons and hydrocarbon mixtures, such as n-pentane, n-hexane, n-heptane, n-octane, 1,2,4-trimethylpentane (isooctane), petroleum ether, special boiling point spirits; cyclohexane, methylcyclohexane are also examples. Mixtures of the above solvents can also be used.

[0032] Preferred solvents are aromatic hydrocarbons and halogenated hydrocarbons, such as difluorobenzene, benzotrifluoride, 4-chlorobenzotrifluoride, benzene, toluene, anisole, o-xylene, m-xylene, p-xylene, industrial xylene, ethylbenzene, mesitylene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, chlorobenzene, bromobenzene, dichlorobenzene, especially 1,2-dichlorobenzene, chlorotoluene, trichlorobenzene, cumene, or mixtures thereof.

[0033] Particularly preferred solvents are chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, industrial xylene, ethylbenzene, or mixtures thereof.

[0034] The most particularly preferred solvents are o-xylene, m-xylene, p-xylene, and industrial xylene.

[0035] In the method according to the present invention, methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate of formula (I) is prepared by reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) with diphosgene or triphosgene.

[0036] The preferred option is triphosgene.

[0037] Triphosgene is preferably used as a solution in a suitable solvent. Suitable solvents are the solvents or solvent mixtures mentioned above.

[0038] Therefore, preferred solvents for triphosgene are aromatic hydrocarbons and halogenated hydrocarbons, such as difluorobenzene, benzotrifluoride, 4-chlorobenzotrifluoride, benzene, toluene, anisole, o-xylene, m-xylene, p-xylene, industrial xylene, ethylbenzene, mesitylene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, chlorobenzene, bromobenzene, dichlorobenzene, especially 1,2-dichlorobenzene, chlorotoluene, trichlorobenzene, cumene, or mixtures thereof.

[0039] Therefore, particularly preferred solvents for triphosgene are chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, industrial xylene, ethylbenzene, or mixtures thereof.

[0040] Therefore, particularly preferred solvents for triphosgene are o-xylene, m-xylene, p-xylene, and industrial xylene.

[0041] However, triphosgene can also be used in solid form or as a molten product.

[0042] When triphosgene is used as a solution, the concentration of triphosgene is in the range of 1-99%, preferably 10-80%, particularly preferably 20-60%, and especially preferably 30-50%. To increase the solubility of triphosgene in the selected solvent, the solvent may be heated.

[0043] The molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate to triphosgene is within the range of 1.0:0.333 to 1.0:1.5, preferably between 1.0:0.333 and 1.0:1.0, particularly preferably between 1.0:0.333 and 1.0:0.7, and especially preferably between 1.0:0.4 and 1.0:0.7.

[0044] The molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate to diphosgene is within the range of 1.0:0.5 to 1.0:2.25, preferably between 1.0:0.5 and 1.0:1.5, particularly preferably between 1.0:0.5 and 1.0:1.05, and especially preferably between 1.0:0.6 and 1.0:1.05.

[0045] The method according to the present invention is carried out in the presence of a catalyst. An alkyl isocyanate may be used as the catalyst. The molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate to the alkyl isocyanate is in the range of 1.0:0.01 to 1.0:2.0, preferably between 1.0:0.05 and 1.0:2.0, and particularly preferably between 1.0:0.05 and 1.0:1.8.

[0046] Preferably used alkyl isocyanates are propyl isocyanate, butyl isocyanate, and pentyl isocyanate. Butyl isocyanate is particularly preferred.

[0047] The reaction generally takes place at a temperature between 20°C and 200°C, preferably between 80°C and 160°C, and particularly preferably between 110°C and 140°C.

[0048] The reaction is typically carried out at standard pressure, but it can also be carried out at high or low pressure (generally 0.1 bar to 10 bar).

[0049] Equation (I) [ka]

[0050] As an intermediate in the method for producing methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate, dimethyl 4,4'-(carbonyl disulfamoyl)bis(5-methylthiophene-3-carboxylate) and, depending on the alkyl isocyanate used, formula (III): [ka]

[0051] [In formula (III), R is alkyl. In formula (III), R is preferably propyl, butyl, and pentyl, and particularly preferably butyl.] The compound is formed.

[0052] These intermediates also react under reaction conditions to give the desired methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate of formula (I).

[0053] A further aspect of the present invention is formula (I): [ka]

[0054] The present invention relates to the use of dimethyl 4,4'-(carbonyl disulfamoyl)bis(5-methylthiophene-3-carboxylate) and / or a compound of formula (III) [wherein formula (III) is alkyl, preferably propyl, butyl or pentyl, particularly preferably butyl] for a method of preparing methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate.

[0055] The compound of formula (I) obtained by the method according to the present invention can be isolated before its use in preparing the final herbicide product. However, it is also possible and advantageous to directly react the obtained compound of formula (I) further without further isolation of the intermediate. The concentration of the reaction solution can be further increased by removing part of the solvent by distillation. Most of the present catalyst can also be recovered.

[0056] In a preferred embodiment, the method for preparing methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate of formula (I) is carried out by reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) with triphosgene in the presence of one or more solvents and catalysts, where the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is in the range of 1.0:0.333 to 1.0:1.5, and the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to catalyst is in the range of 1.0:0.01 to 1.0:2.0. The molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is preferably in the range of 1.0:0.333 to 1.0:0.7, and more preferably in the range of 1.0:0.4 to 1.0:0.7. The molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is preferably in the range of 1.0:0.05 to 1.0:2.0, and more preferably in the range of 1.0:0.05 to 1.0:1.8. The catalyst used may be an alkyl isocyanate, preferably n-butyl isocyanate, propyl isocyanate, or pentyl isocyanate, and particularly preferably n-butyl isocyanate. The solvent used may be chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, industrial xylene, ethylbenzene, or mixtures thereof, preferably o-xylene, m-xylene, p-xylene, industrial xylene, or mixtures thereof. This method can be carried out at a temperature between 20 and 200°C, preferably 80 and 160°C, and especially preferably 110 and 140°C.

[0057] In a more preferred embodiment, the method for preparing methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate of formula (I) is carried out by reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) with triphosgene in the presence of one or more solvents and a catalyst, where the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is in the range of 1.0:0.333 to 1.0:1.5, and the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0:0.01 to 1.0:2.0. The molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is preferably in the range of 1.0:0.333 to 1.0:0.7, preferably in the range of 1.0:0.4 to 1.0:0.7, and the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is preferably in the range of 1.0:0.05 to 1.0:2.0, preferably in the range of 1.0:0.05 to 1.0:1.8. The catalyst used may be an alkyl isocyanate, preferably n-butyl isocyanate, propyl isocyanate, or pentyl isocyanate, and particularly preferably n-butyl isocyanate. The solvent used may be chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, industrial xylene, ethylbenzene, or a mixture thereof, preferably o-xylene, m-xylene, p-xylene, industrial xylene, or a mixture thereof. This method can be carried out at a temperature of 20 to 200°C, preferably 80 to 160°C, and particularly preferably 110 to 140°C.

[0058] In a particularly preferred embodiment, the method for preparing methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate of formula (I) is carried out by reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) with triphosgene in the presence of one or more solvents and a catalyst, where the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is in the range of 1.0:0.333 to 1.0:0.7, and the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0:0.05 to 1.0:2.0. The catalyst used may be an alkyl isocyanate, preferably n-butyl isocyanate, propyl isocyanate, or pentyl isocyanate, particularly preferably n-butyl isocyanate. The solvent used may be o-xylene, m-xylene, p-xylene, industrial xylene, or a mixture thereof. This method can be carried out at a temperature between 20 and 200°C, preferably 80 and 160°C, and particularly preferably 110 and 140°C.

[0059] In a very particularly preferred embodiment, a method for preparing methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate of formula (I) is carried out by reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) with triphosgene in the presence of one or more solvents and a catalyst, where the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is in the range of 1.0:0.4 to 1.0:0.7, and the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0:0.05 to 1.0:1.8. The catalyst used may be an alkyl isocyanate, preferably n-butyl isocyanate, propyl isocyanate, or pentyl isocyanate, particularly preferably n-butyl isocyanate. The solvent used may be o-xylene, m-xylene, p-xylene, industrial xylene, or a mixture thereof. This method can be carried out at a temperature between 20°C and 200°C, preferably between 80°C and 160°C, and particularly preferably between 110°C and 140°C. The present invention will be described in more detail with reference to the following examples, but these examples should not be construed as limiting the present invention. [Examples]

[0060] Examples: The reported yield was calculated by weighing the obtained organic phase and correcting this weight by the content in weight percent determined by HPLC. For HPLC measurement, a sample of the product solution was reacted with anhydrous methanol, thereby derivatizing the present methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate to obtain methyl 4-(methoxycarbonylsulfamoyl)-5-methylthiophene-3-carboxylate. The weight percent of this compound was determined relative to methyl 4-(methoxycarbonylsulfamoyl)-5-methylthiophene-3-carboxylate as an external standard and then used to estimate the proportion of methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate in the product phase.

[0061] Example 1: Synthesis of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate using 1.0 equivalent of n-butyl isocyanate and 0.5 equivalents of triphosgene (concentration: 9.9 wt%) A 250 ml glass reactor equipped with an overhead stirrer, gas inlet, metering and addition line, and reflux condenser was used.

[0062] The reflux condenser was cooled to -15°C. 19.1 g (98.6%, 80.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate and 173 g of xylene were packed into the reactor, which had been initially purged with nitrogen. The mixture was heated to 136°C with stirring. 8.12 g (98%, 80.3 mmol) of n-butyl isocyanate was added at an internal temperature of 100°C. To the clear reaction solution, 44.2 g of a solution of 12.2 g (98%, 40.2 mmol) of triphosgene in xylene was uniformly weighed and added over a period of 135 minutes or more. After the addition was complete, the weighing line was rinsed with 7.2 g of xylene, and the mixture was stirred at 135-136°C for 4 hours and 31 minutes. The reaction mixture was then cooled to room temperature, and the reflux condenser was warmed to 20°C. The phosgene residue was removed by introducing a nitrogen stream. 220.2 g of a solution of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate in xylene was obtained. The proportion of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate was determined to be 8.7% after derivatization by quantitative HPLC (against an external standard). This corresponds to a yield of 92% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0063] Example 2: Synthesis of methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate using 1.0 equivalent of n-butyl isocyanate and 0.7 equivalents of triphosgene (concentration: 9.9 wt%) A 250 ml glass reactor equipped with an overhead stirrer, gas inlet, metering and addition line, and reflux condenser was used.

[0064] The reflux condenser was cooled to -15°C. 19.1 g (98.6%, 80.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate and 173 g of xylene were packed into the reactor, which had been initially purged with nitrogen. The mixture was heated to 137°C with stirring. 8.1 g (98%, 81 mmol) of n-butyl isocyanate was added at an internal temperature of 104°C. To the clear reaction solution, 68.1 g of a solution of 17.1 g (98%, 56.2 mmol) of triphosgene in xylene was uniformly weighed and added over a period of 106 minutes or more. After the addition was complete, the weighing line was rinsed with 7.9 g of xylene, and the mixture was stirred at 119-135°C for 4 hours and 30 minutes. The reaction mixture was then cooled to room temperature, and the reflux condenser was warmed to 20°C. The phosgene residue was removed by introducing a nitrogen stream. 233.8 g of a solution of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate in xylene was obtained. The proportion of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate was determined to be 8.6% after derivatization by quantitative HPLC (against an external standard). This corresponds to a 95% yield starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0065] Example 3: Synthesis of methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate using 0.5 equivalents of n-butyl isocyanate and 0.5 equivalents of triphosgene at a high concentration (concentration: 20% by weight) in the reaction solution. A 250 ml glass reactor equipped with an overhead stirrer, gas inlet, metering and addition line, and reflux condenser was used. The reflux condenser was cooled to -15°C. 31.0 g (98.6%, 130.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate and 124.1 g of xylene were packed into the reactor, which had been initially purged with nitrogen. The mixture was heated to 137°C with stirring. 6.7 g (98%, 66 mmol) of n-butyl isocyanate was added at an internal temperature of 102°C. To the clear reaction solution, 78.7 g of a solution of 19.6 g (98%, 64.7 mmol) of triphosgene in xylene was uniformly weighed and added over a period of 116 minutes or more. After the addition was complete, the weighing line was rinsed with 7.6 g of xylene, and the mixture was stirred at 135-136°C for 2 hours and 32 minutes. The reaction mixture was then cooled to room temperature, and the reflux condenser was warmed to 20°C. The phosgene residue was removed by introducing a nitrogen stream. 225.3 g of a solution of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate in xylene was obtained. The proportion of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate was determined to be 13.8% after derivatization by quantitative HPLC (against an external standard). This corresponds to a yield of 92% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0066] Example 4: Synthesis of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate using 0.5 equivalents of n-butyl isocyanate and 0.7 equivalents of triphosgene at a high concentration (concentration: 20% by weight) in the reaction solution. A 250 ml glass reactor equipped with an overhead stirrer, gas inlet, metering and addition line, and reflux condenser was used.

[0067] The reflux condenser was cooled to -15°C. 31.0 g (98.6%, 130.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate and 124.1 g of xylene were packed into the reactor, which had been initially purged with nitrogen. The mixture was heated to 137°C with stirring. 6.6 g (98%, 65 mmol) of n-butyl isocyanate was added at an internal temperature of 102°C. To the clear reaction solution, 110.4 g of a solution of 27.6 g (98%, 91.1 mmol) of triphosgene in xylene was uniformly weighed and added over a period of 118 minutes or more. After the addition was complete, the weighing line was rinsed with 9.6 g of xylene, and the mixture was stirred at 124-132°C for 3 hours and 11 minutes. The reaction mixture was then cooled to room temperature, and the reflux condenser was warmed to 20°C. The phosgene residue was removed by introducing a nitrogen stream. 180.9 g of a solution of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate in xylene was obtained. The proportion of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate was determined to be 17.7% after derivatization by quantitative HPLC (against an external standard). This corresponds to a yield of 94% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0068] Example 5: Synthesis of methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate using 0.3 equivalents of n-butyl isocyanate and 0.7 equivalents of triphosgene at a high concentration (concentration: 25 wt%) in the reaction solution. A 250 ml glass reactor equipped with an overhead stirrer, gas inlet, metering and addition line, and reflux condenser was used.

[0069] The reflux condenser was cooled to -15°C. 30.83 g (99.2%, 130.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate, 91.33 g of xylene, and 3.95 g (98%, 39.0 mmol) of n-butyl isocyanate were added to a reactor that had been initially purged with nitrogen. The mixture was heated to 139°C with stirring. 90.6 g of a solution of 27.6 g (98%, 91.1 mmol) of triphosgene in xylene was uniformly weighed into the clear reaction solution over a period of 183 minutes or more. After the addition was complete, the weighing line was rinsed with 9.6 g of xylene, and the mixture was stirred at 125-139°C for 3 hours and 4 minutes. The reaction mixture was then cooled to room temperature, and the reflux condenser was warmed to 20°C. The phosgene residue was removed by introducing a nitrogen stream. 182.8 g of a solution of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate in xylene was obtained. The proportion of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate was determined to be 17.0% after derivatization by quantitative HPLC (against an external standard). This corresponds to a yield of 92% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0070] Example 6: Synthesis of methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate using 0.25 equivalents of n-butyl isocyanate and 0.7 equivalents of triphosgene at a high concentration (concentration: 30% by weight) in the reaction solution. A 250 ml glass reactor equipped with an overhead stirrer, gas inlet, metering and addition line, and reflux condenser was used.

[0071] The reflux condenser was cooled to -15°C. 30.83 g (99.2%, 130.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate, 71.20 g of xylene, and 3.29 g (98%, 32.5 mmol) of n-butyl isocyanate were placed in a reactor that had been initially purged with nitrogen. The mixture was heated to 139°C with stirring. To the clear reaction solution, 90.6 g of a solution of 27.6 g (98%, 91.1 mmol) of triphosgene in xylene was uniformly weighed and added over a period of 245 minutes or more. After the addition was complete, the weighing line was rinsed with 9.6 g of xylene, and the mixture was stirred at 124-130°C for 2 hours and 57 minutes. The reaction mixture was then cooled to room temperature, and the reflux condenser was warmed to 20°C. The phosgene residue was removed by introducing a nitrogen stream. 158.9 g of a solution of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate in xylene was obtained. The proportion of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate was determined to be 19.5% after derivatization by quantitative HPLC (against an external standard). This corresponds to a yield of 91% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0072] Example 7: Synthesis of methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate using 0.25 equivalents of n-butyl isocyanate and 0.6 equivalents of triphosgene at a high concentration (concentration: 30% by weight) in the reaction solution. The experiment was carried out as described in Example 6, but with the difference being the use of a solution of 23.6 g (98%, 77.9 mmol) of triphosgene in 42.5 g of xylene. 169.9 g of a solution of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate in xylene was obtained. The proportion of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate was determined to be 18.6% after derivatization by quantitative HPLC (against an external standard). This corresponds to a 93% yield starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0073] Example 8: Synthesis of methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate using 0.25 equivalents of n-butyl isocyanate and 0.6 equivalents of triphosgene at a high concentration (concentration: 35 wt%) in the reaction solution. A 250 ml glass reactor equipped with an overhead stirrer, gas inlet, metering and addition line, and reflux condenser was used.

[0074] The reflux condenser was cooled to -15°C. 30.83 g (99.2%, 130.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate, 57.20 g of xylene, and 3.29 g (98%, 32.5 mmol) of n-butyl isocyanate were placed in a reactor that had been initially purged with nitrogen. The mixture was heated to 139°C with stirring. To the clear reaction solution, 77.1 g of a solution of 23.6 g (98%, 77.9 mmol) of triphosgene in xylene was uniformly weighed and added over 238 minutes or more. After the addition was complete, the weighing line was rinsed with 9.6 g of xylene, and the mixture was stirred at 138-130°C for 3 hours and 2 minutes. The reaction mixture was then cooled to room temperature, and the reflux condenser was warmed to 20°C. The phosgene residue was removed by introducing a nitrogen stream. 124.3 g of a solution of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate in xylene was obtained. The proportion of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate was determined to be 25.0% after derivatization by quantitative HPLC (against an external standard). This corresponds to a yield of 92% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0075] Comparative Example 1: Synthesis of methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate using 1.0 equivalent of n-butyl isocyanate and 2.1 equivalents of phosgene (concentration: 10% by weight) A 500 ml glass reactor equipped with an overhead stirrer, gas inlet, and reflux condenser was used.

[0076] The reflux condenser was cooled to -12°C. 30.0 g (127.5 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate and 270 g of xylene were packed into the reactor, which had been initially purged with nitrogen. The mixture was heated to 140°C with stirring. 12.6 g (127.5 mmol) of n-butyl isocyanate was added at an internal temperature of 100°C. 26.5 g (268 mmol) of phosgene was introduced into the clear reaction solution over 3 hours. After the addition was complete, the mixture was stirred for 1 hour and 30 minutes. The reaction mixture was then cooled to room temperature. The phosgene residue was removed by introducing an argon stream. 304.1 g of a solution of methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate in xylene was obtained. The proportion of methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate was determined to be 9.7% by quantitative HPLC (against an external standard) after derivatization. This corresponds to an 89% yield starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0077] The yield was 6 percentage points lower than in Example 2, which used the same amount of phosgene equivalent.

[0078] The following compounds were identified as intermediates in this method: Dimethyl 4,4'-(carbonyl disulfamoyl)bis(5-methylthiophene-3-carboxylate) MS (ESI negative): m / z = 495.1 [MH] - Methyl 4-[(butylcarbamoyl)sulfamoyl]-5-methylthiophene-3-carboxylate MS (ESI negative): m / z = 333.2 [MH] -

Claims

1. Formula (II): 【Chemistry 1】 By reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate with diphosgene or triphosgene in the presence of one or more solvents and catalysts, formula (I) is obtained: 【Chemistry 2】 A method for preparing methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate, wherein, - With respect to diphosgene, is the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to diphosgene within the range of 1.0:0.5 to 1.0:2.25? or - With respect to triphosgene, the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is in the range of 1.0:0.333 to 1.0:1.5; The method wherein the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0:0.01 to 1.0:2.

0.

2. The method according to claim 1, wherein triphosgene is used, and the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is in the range of 1.0:0.333 to 1.0:0.7, preferably in the range of 1.0:0.4 to 1.0:0.

7.

3. The method according to claim 1 or 2, wherein the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0:0.05 to 1.0:2.0, preferably in the range of 1.0:0.05 to 1.0:1.

8.

4. The method according to any one of claims 1 to 3, wherein an alkyl isocyanate is used as a catalyst.

5. The method according to claim 4, wherein the alkyl isocyanate is n-butyl isocyanate, propyl isocyanate, or pentyl isocyanate.

6. The method according to claim 5, wherein the alkyl isocyanate is n-butyl isocyanate.

7. The method according to any one of claims 1 to 6, wherein chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, industrial xylene, ethylbenzene, or a mixture thereof is used as a solvent.

8. The method according to claim 7, wherein o-xylene, m-xylene, p-xylene, industrial xylene, or a mixture thereof is used as a solvent.

9. The method according to any one of claims 1 to 8, wherein the method is carried out at a temperature between 20°C and 200°C, preferably between 80°C and 160°C, and particularly preferably between 110°C and 140°C.

10. As an intermediate of the above method, dimethyl 4,4'-(carbonyl disulfamoyl)bis(5-methylthiophene-3-carboxylate) and, depending on the alkyl isocyanate used, formula (III): 【Transformation 3】 [In formula (III), R is alkyl.] The method according to any one of claims 1 to 9, wherein the compound is formed.

11. The method according to claim 10, wherein R is propyl, butyl, or pentyl in formula (III).

12. The method according to claim 11, wherein R is butyl in formula (III).

13. Equation (I): 【Chemistry 4】 For a method of preparing methyl 4-isocyanathosulfonyl-5-methylthiophene-3-carboxylate, use of dimethyl 4,4'-(carbonyl disulfamoyl)bis(5-methylthiophene-3-carboxylate) and / or a compound of formula (III) [wherein formula (III), R is alkyl, preferably propyl, butyl or pentyl, particularly preferably butyl].

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